NZ538834A - Pharmaceutical compositions for inhalation containing a new anticholinergic in conjunction with corticosteroids and betamimetics - Google Patents

Abstract

Disclosed herein are pharmaceutical compositions that are suitable as inhalation medicaments, wherein the compositions comprise at least one anticholinesterase compound of formula (I), at least one corticosteroid and at least one betamimetic drug. These pharmaceutical compositions are suitable for use in the treatment of respiratory illnesses.

Description

Inhalation medicament containing a novel anticholinesterase drug in conjunction with corticosteroids and betamimetic drugs The present invention relates to novel pharmaceutical compositions based on a new anticholinergic, corticosteroids and betamimetics, processes for preparing them and their use in the treatment of respiratory diseases.

Description of the invention The present invention relates to novel pharmaceutical compositions for inhalation based on a new anticholinergic, corticosteroids and betamimetics, processes for preparing them and their use in the treatment of respiratory diseases.

Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic 15 effect can be observed in the treatment of inflammatory or obstructive diseases of the respiratory tract if a new anticholinergic is used with one or more corticosteroids and with one or more betamimetics. In view of this synergistic effect the pharmaceutical combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way. This 20 reduces unwanted side effects such as may occur when corticosteroids and betamimetics are administered, for example.

The effects mentioned above may be observed both when the three active substances are administered simultaneously in a single active substance formulation and when they are administered successively in separate formulations. According to 25 the invention, it is preferable to administer the active substance ingredients simultaneously in a single formulation. The pharmaceutical compositions according to the invention are preferably administered by inhalation according to the invention.

Within the scope of the present invention the anticholinergics used are the salts of formula 1 intellectual property office of n.z. 31 JUL 2007 received Mev + Me \ / N ^ 1 wherein X " denotes an anion with a single negative charge, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

Preferably, the salts of formula 1 are used wherein 10 X" denotes an anion with a single negative charge selected from the group consisting of chloride, bromide, 4-toluenesulphonate and methanesulphonate, preferably bromide.

Most preferably, the salts of formula 1 are used wherein 15 X" denotes an anion with a single negative charge selected from the group consisting of chloride, bromide and methanesulphonate, preferably bromide.

Particularly preferred according to the invention is the salt of formula i wherein ^20 X" denotes bromide.

The salts of formula 1 are known from International Patent Application WO 02/32899. Any reference to the salts of formula Ijncludes a reference to any hydrates and solvates thereof which may be obtained.

Within the scope of the present patent application, an explicit reference to the pharmacologically active cation of formula can be recognised by the use of the designation V. Any reference to compounds 1 naturally includes a reference to the cation V.

Within the scope of the present invention, the word corticosteroids (hereinafter 2) denotes compounds selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. Preferably, compound 2 is selected from among flunisolide, beclomethasone, triamcinolone, budesonide, 10 fluticasone, mometasone, ciclesonide and dexamethasone. Most preferably, compound 2 is selected from among budesonide, fluticasone, mometasone and ciclesonide. In some cases, within the scope of the present patent application, the term steroids 2 may also be used on its own instead of the word corticosteroids 2.

Any reference to steroids 2 within the scope of the present invention includes a 15 reference to salts or derivatives T which may be formed from the steroids. Examples of possible salts or derivatives 2_ include: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. In some cases the compounds of formula 2 may also occur in the form of their hydrates.

Examples of betamimetics 3 which may be used according to the invention include bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-25 amino}ethyl3-2(3H)-benzothiazolone, 1 -(2-fluoro-4-hydroxyphenyl)-2-[4-(1 - benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl- 4 2-propylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-ylj-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-5 2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1 -hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1 -(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol or 1 -(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol.

According to the invention the following betamimetics 3 are preferably used in the active substance combination: formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 15 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-20 propylaminojethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylaminojethanol or 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol.

Salmeterol salts or formoterol salts are preferably used as the long-acting betamimetics 3 according to the invention. Any reference to the term betamimetics 3 also includes a reference to the relevant enantiomers or mixtures thereof. For example, any reference to the preferred compounds 3 according to the invention, the 30 salts of salmeterol and formoterol, also includes the relevant enantiomeric salts of R-salmeterol, S-salmeterol, R,R-formoterol, S,S-formoterol, R,S-formoterol, S,R-formoterol and the mixtures thereof, while the enantiomeric salts of R-salmeterol and R,R-formoterol are of particular importance. The compounds 3 may also be present according to the invention in the form of the hydrates or solvates thereof.

Within the scope of the present invention any reference to compounds 3 is to be understood as being a reference to physiologically acceptable acid addition salts. By physiologically acceptable acid addition salts of the betamimetics 3 are meant according to the invention pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 3.

According to the invention the salts of the betamimetics 3 selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate and xinafoate are preferred. Particularly preferably, in the case of salmeterol, the salts of 3 are selected from those salts which have a solubility in water of 0.1 mg/ml 10 or less, preferably 0.05 mg/ml or less, most preferably 0.04 mg/ml or less. In this context xinafoate, 4-phenylcinnamate and diflunisal are mentioned as particularly preferred salts of salmeterol. Particularly preferred salts 3 of salmeterol have a solubility in water of 0.035 mg/ml or less, such as for example 4-phenylcinnamate or diflunisal.

Particularly preferably, in the case of formoterol, the salts of 3 are selected from the hydrochloride, sulphate and fumarate, of which the hydrochloride and fumarate are particularly preferred. Of exceptional importance according to the invention is formoterol fumarate.

If, within the scope of the present invention, there is a reference to betamimetics which are not in the salt form, this can be taken to mean a reference to compounds 3\ For example, the preferred betamimetics 3^ according to the invention which are not in salt form are the free base of formoterol or salmeterol, whereas the particularly preferred compounds 3 according to the invention are, for example, salmeterol 25 xinafoate, salmeterol 4-phenylcinnamate or formoterol fumarate.

\ Within the scope of the present invention the betamimetics 3 are optionally also referred to as sympathomimetics or beta-2-receptor agonists (^-agonists). All these names can be regarded as equivalent within the scope of the present invention.

The pharmaceutical combinations of 1^ 2 and 3 according to the invention are preferably administered by inhalation. Suitable inhalable powders packed into suitable capsules (inhalettes) may be administered using suitable powder inhalers.

Accordingly, in one aspect, the present invention relates to a pharmaceutical 35 composition which contains a combination of ^ 2 and 3 . 6 In another aspect the present invention relates to a pharmaceutical composition which contains one or more salts 1, one or more compounds 2 and one or more compounds 3, optionally in the form of their solvates or hydrates. The active substances may be combined in a single preparation or contained in two or three 5 separate formulations. Pharmaceutical compositions which contain the active substances 2 and 3 in a single preparation are preferred according to the invention.

In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of 1^ 2 and 3, a 10 pharmaceutical^ acceptable excipient. In another aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of 2 and 3.

The present invention also relates to the use of 1^ 2 and 3 for preparing a pharmaceutical composition containing therapeutically effective quantities of 2 and 15 3 for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma and/or chronic obstructive pulmonary disease (COPD), by simultaneous or successive administration. In addition the pharmaceutical combinations according to the invention may be used to prepare a drug for treating cystic fibrosis or allergic alveolitis (farmer's lung), for example, by simultaneous or 20 successive administration. The combinations of active substances according to the invention will not be used only if treatment with one of the pharmaceutically active ingredients is contraindicated.

The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 2 and 3 for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma and/or chronic obstructive pulmonary disease (COPD), provided that treatment with steroids or betamimetics is not contraindicated from a therapeutic point of view, by simultaneous or successive administration. The invention further relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions Ij, 2 and 3 for treating cystic fibrosis or allergic alveolitis (farmer's lung).

In the active substance combinations of 1^ 2 and 3 according to the invention, ingredients 2 and 3 may be present in the form of their enantiomers, mixtures of 35 enantiomers or in the form of racemates. For example, the pharmaceutical 7 compositions according to the invention contain the active substances 1^ 2 and 3 according to the invention in amounts such that a single administration corresponds to a dosage of the combination of active substances ^ 2 and 3pf 1 to 10000 (jg, preferably from 10 to 2000 |jg.

The proportions in which the active substances 2 and 3 may be used in the active substance combinations according to the invention are variable. Active substances 1^ 2 and 3 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 1^ 2 and 3, the weight ratios which may be used within the scope of the present invention vary on the basis of the different 10 molecular weights of the various compounds and their different potencies. As a rule, the pharmaceutical combinations according to the invention may contain compounds V_ and 2 in ratios by weight ranging from 1:250 to 250:1, preferably from 1:150 to 150:1. In the particularly preferred pharmaceutical combinations which contain in addition to V a compound selected from among budesonide, fluticasone, 15 mometasone and ciclesonide as steroid 2, the weight ratios of V to 2 are most preferably in a range from about 1:40 to 40:1, more preferably in the range from 1:30 to 30:1.

For example, without restricting the scope of the invention thereto, preferred 20 combinations of 1 and 2 according to the invention may contain the cation V_ and one of the abovementioned preferred steroids 2 in the following proportions by weight: 1:20; 1:19; 1:18; 1:17; 1:16; 1:15; 1:14; 1:13; 1:12; 1:11; 1:10; 1:9; 1:8; 1:7; 1:6; 1:5; 1:4; 1:3; 1:2; 1:1; 2:1; 3:1; 4:1; 5:1; 6:1; 7:1; 8:1; 9:1; 10:1; 11:1; 12:1; 13:1; 14:1; 15:1; 16:1; 17:1; 18:1; 19:1; 20:1.

The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally administered so that V_ and 2 are present together in doses of 5 to 5000|jg, preferably from 10 to 2000|jg, more preferably from 15 to 1000|jg, even more preferably from 20 to 800|jg, preferably according to the 30 invention from 30 to 700[jg, preferably from 40 to 600(jg, preferably from 50 to 500 pg, preferably from 40 to 500 |jg, more preferably from 50 to 400 |jg per single dose. For example, combinations of 1 and 2 according to the invention contain a quantity of V and steroid 2 such that the total dosage per single dose is about 35[jg, 45[jg, 50pg, 55(jg, 60[jg, 65pg, 70|jg, 75|jg, 80[jg, 85(jg, 90|jg, 95|jg, 100|jg, 105jjg, 110[jg, 35 115jjg, 120(jg, 125pg, 130|jg, 135(jg,140 |jg,145jjg, 150|jg,155|jg, 160|jg, 165Mg, 170|jg, 175Mg, 180Mg, 185|jg, 190|jg, 195|jg, 200|jg, 205jjg, 210pg, 215jjg, 220|jg, 225(jg, 230(jg, 235(jg, 240|jg, 245(jg, 250|jg, 255(jg, 260|jg, 265|jg, 270|jg, 275|jg, 280(jg, 285|jg, 290(jg, 295|jg, 300jjg, 305(jg, 310pg, 315|jg, 320(jg, 325|jg, 330|jg, 8 335[jg, 340pg, 345pg, 350pg, 355(jg, 360|jg, 365pg, 370pg, 375pg, 380|jg, 385(jg, 390pg, 395pg, 400|jg, 405pg, 410pg, 415|jg, 420pg, 425pg, 430|jg, 435|jg, 440pg, 445pg, 450(jg, 455|jg, 460pg, 465|jg, 470pg, 475pg, 480pg, 485ijg, 490ijg, 495pg, 500pg, 505pg, 510}jg, 515pg, 520pg, 525pg, 530pg, 535|jg, 540pg, 545pg, 550ijg, 5 555|jg, 560|jg, 565|jg, 570pg, 575pg, 580pg, 585|jg, 590pg, 595|jg, 600[jg, 605|jg, 610pg or the like. It is clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the numerical values explicitly mentioned. Fluctuations of around ± 2.5|jg , particularly fluctuations in the decimal range, are also covered as will be apparent to anyone skilled in the art. In 10 these dosage ranges the active substances Y and 2 may be present in the weight ratios described above.

For example and without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain an amount of cation '15 Y and steroid 2 such that each single dose contains 16.5|jg of Y and 25pg of 2, 16.5pg of 1^ and 25pg of 2, 16.5pg of Y and 50pg of 2, 16.5|jg of Y and 100pg of 2, 16.5pg of Y and 150|jg of 2, 16.5|jg of Y and 200pg of 2, 16.5jjg of Y and 250pg of 2, 33.0pg of Y and 25pg of 2, 33.0pg of Y and 50pg of 2, 33.0pg of Y and 100(jg of 2, 33.0pg of Y and 150[jg of 2, 33.0Mg of Y and 200[jg of 2, 33.0|jg 20 of Y and 250[jg of 2, 49.5 pg of Y and 25pg of 2, 49.5(jg of Y and 50(jg of 2, 49.5pg of Y and 100pg of 2, 49.5|jg of Y and 150pg of 2, 49.5pg of 1^ and 200pg of 2, 49.5pg of Y and 250pg of 2, 82.6[jg of Y and 25pg of 2, 82.6(jg of Y and 50pg of 2, 82.6pg of Y and 100pg of 2, 82.6pg of Y and 150^g of 2, 82.6pg of Y and 200pg of 2, 82.6pg of Y and 250|jg of 2, 165.1 (jg of Y and 25pg of 2, 25 165.1 (jg of Y and 50|jg of 2, 165.1 pg of Y and 50pg of 2, 165.1 pg of Y and 100pgof 2, 165.1pgof 1^and150pgof 2, 165.1pgof Vand200pgof 2, 165.1pg of Y and 250pg of 2, 206.4pg of Y and 25pg of 2, 206.4pg of Y and 50jjg of 2, 206.4pg of Y and 100(jg of 2, 206.4pg of Y and 150pg of 2, 206.4|jg of Y and 200pg of 2, 206.4pg of Y and 250pg of 2, 412.8pg of Y and 25pg of 2, 412.8|jg of 30 Y and 50pg of 2, 412.8jjg of Y and 100pg of 2, 412.8pg of Y and 150(jg of 2, 412.8ijg of Y and 200pg of 2, 412.8(jg of Y and 250pg of 2.

If the active substance combination wherein the bromide is used as the salt 1 and 2 denotes one of the preferred steroids disclosed hereinbefore is used as a preferred 35 combination of 1 and 2 according to the invention, the quantities of active substances 1^ and 2 administered per single dose as specified by way of example correspond to the following quantities of 1 and 2 administered per single dose: 20pg of 1 and 25pg of 2, 20pg of 1 and 50pg of 2, 20pg of 1 and 100ng of 2, 20pg of 1 and 150pg of 2, 20pg of 1 and 200pg of 2, 20pg of 1 and 250pg of 2, 40(jg of 1 and 25pg of 2, 40|jg of 1 and 25[jg of 2, 40|jg of 1 and 50pg of 2, 40pg of 1 and 10Ojjg of 2, 40pg of 1 and 150pg of 2, 40pg of 1 and 200}jg of 2, 40jjg of 1 and 250pg of 2, 60|jg of 1 and 25|jg of 2, 60(jg of 1 and 50(jg of 2, 60|jg of 1 and 100}jg of 2, 60pg of 1 and 150(jg of 2, 60jjg of 1 and 200|jg of 2, 60|jg of 1 and 250|jg of 2, 100pg of 1 and 25pg of 2, 100|jg of 1 and 50|jg of 2, 100pg of 1 and 100|jg of 2, 10Opg of 1 and 150pg of 2, 10Ojjg of I and 200pg of 2, 1OOpg of 1 and 250pg of 2, 200pg of i and 25pg of 2, 200pg of 1 and 50pg of 2, 200(jg of 1 and 10Ofjg of 2, 200(jg of i and 150(jg of 2, 200|jg of 1 and 200pg of 2, 200|jg of I and 250|jg of 2, 250|jg of 1 and 25(jg of 2, 250|jg of 1 and 50|jg of 2, 250|jg of 1 and 100}jg of 2, 250|jg of 1 and 150|jg of 2, 250}jg of 1 and 200pg of 2, 250pg of i and 250(jg of 2, 500(jg of 1 and 25|jg of 2, 500|jg of 1 and 50pg of 2, 500pg of 1 and 100(jg of 2, 500jjg of 1 and 150|jg of 2, 500|jg of 1 and 200jjg of 2, 500|jg of 1 and 250[jg of 2.

At the same time the ratio of 1 to 3 may be1:300 to 30:1, preferably from 1:230 to 20:1, more preferably from 1:150 to 10:1, still more preferably from 1:50 to 5:1, more preferably from 1:35 to 2:1.

In the case of formoterol, for example, the active substance combinations according 20 to the invention may contain V and 3^ in ratios by weight which are, for example, in the range from about 1:10 to 300:1, preferably 1:5 to 200:1, preferably 1:3 to 150:1, more preferably from 1:2 to 100:1.

For example and without restricting the scope of the invention thereto, preferred combinations of 1 and 3 according to the invention contain the pharmacologically active cation Y and formoterol 3^ in the following ratios by weight: 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24 33:1, 34:1, 35:1, 36:1, 37:1, 38:1, 39 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54 63:1, 64:1, 65:1, 66:1, 67:1, 68:1, 69 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99 1, 10 1,25 1,40 1, 55 1, 70 1, 85:1, 86 1, 100:1. 1, 14:1, 15:1, 16:1, 17 1, 29:1, 30:1, 31:1, 32 1,44:1,45:1,46:1,47 1, 59:1,60:1,61:1,62 1,74:1,75:1,76:1,77 1, 87:1, 88:1, 89:1, 90:1, 91:1, 92 1,11 1, 12 1, 13 1, 26 1,27 1, 28 1,41 1, 42 1, 43 1, 56 1, 57 1, 58 1, 71 1, 72 1,73 The pharmaceutical compositions according to the invention containing the combinations of 1 and 3 are normally used so that the pharmacologically active cation Y and formoterol 3^ are present together in doses from 5 to 5000pg, preferably from 10 to 2000jjg, more preferably from 15 to 1000^ig, still more preferably from 20 to 800|jg, preferably according to the invention from 30 to 600pg, preferably from 40 to 500(jg.

For example, the combinations of 1 and 3 according to the invention contain an 5 amount of cation V and formoterol 3^ such that the total dosage per single dose is about 10pg, 15|jg, 20pg, 25pg, 30pg, 35pg, 45pg, 50pg, 55pg, 60pg, 65|jg, 70|jg, 75[jg, 80pg, 85pg, 90pg, 95|jg, 100pg, 105(jg, 110|jg, 115(jg, 120|jg, 125|jg, 130pg, 135pg, 140(jg, 145pg, 150|jg, 155pg, 160pg, 165pg, 170[jg, 175|jg, 180|jg, 185|jg, 190pg, 195pg, 200pg, 205|jg, 210pg, 215pg, 220pg, 225pg, 230|jg, 235|jg, 240pg, 10 245pg, 250pg, 255ijg, 260pg, 265pg, 270pg, 275pg, 280pg, 285|jg, 290pg, 295pg, 300(jg, 305pg, 310pg, 315pg, 320pg, 325pg, 330pg, 335(jg, 340pg, 345|jg, 350pg, 355pg, 360pg, 365|jg, 370|jg, 375|jg, 380ijg, 385pg, 390pg, 395|jg, 400(jg, 405|jg, 410(jg, 415pg, 420pg, 425pg, 430pg, 435|jg, 440|jg, 445|jg, 450|jg, 455[jg, 460|jg, ^ 465pg, 470pg, 475pg, 480jjg, 485pg, 490pg, 495pg, 500pg, 505|jg, 510pg, 515pg, 15 520pg, 525pg, 530pg, 535pg, 540|jg, 545pg, 550pg, 555pg, 560(jg, 565pg, 570pg, 575(jg, 580|jg, 585pg, 590pg, 595pg, 600|jg, or similar. It is clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the numerical values explicitly mentioned. Fluctuations of around ± 2.5|jg, particularly fluctuations in the decimal range, are also covered as will be 20 apparent to anyone skilled in the art. In these dosage ranges the active substances Y and y are present in the weight ratios described above.

For example and without restricting the scope of the invention thereto, the combinations of 1 and 3 according to the invention contain an amount of cation Y 25 and formoterol 3^ such that they contain, per single dose, for example 8.3pg of Y_ and 2.5pg of y, 8.3pg of Y and 4.9pg of y, 8.3jjg of Y and 9.8pg of 3f, 8.3|jg of ) Y and 14.7pg of 3^, 8.3pg of Y and 19.6|jg of 3^, 8.3pg of V and 24.4pg of 3^, 16.5pg of Y and 2.5pg of 16.5pg of Y and 4.9pg of y, 16.5pg of Y and 9.8|jg of 3^, 16.5jjg of Y and 14.7pg of 16.5pg of Y and 19.6pg of 3^, 16.5|jg of Y 30 and 24.4pg of 3^, 33.0pg of Y and 2.5pg of y, 33.0pg of Y and 4.9(jg of 3^, 33.0pg of Y and 9.8|jg of y, 33.0|jg of Y and 14.7|jg of 3^, 33.0|jg of Y and 19.6pg of 3^, 33.0pg of Y and 24.4pg of 3^, 49.5pg of Y_ and 2.5(jg of 3^, 49.5pg of Y and 4.9pg of 3^, 49.5pg of Y and 9.8pg of 3^, 49.5pg of Y and 14.7pg of 3^, 49.5pg of Y and 19.6pg of 3^, 49.5pg of Y and 24.4pg of 3^, 82.6pg of Y and 2.5pg of 3^, 82.6pg of 35 Y and 4.9|jg of 3^, 82.6(jg of Y and 9.8(jg of 3^, 82.6|jg of Y and 14.7|jg of 3^, 82.6pg of Y and 19.6pg of 3^, 82.6pg of Y and 24.4pg of 3^, 165.1 pg of Y and 2.5pgof y, 165.1pgof Vand4.9pgof 3^, 165.1pgof Y and 9.8(jg of T, 165.1pg of Y and 14.7[jg of 3^, 165.1 pg of Y and 19.6pg of 3^, 165.1 pg of Vand24.4pgof 3^, 206.4pg of Y and 2.5pg of 3^, 206.4pg of JT and 4.9pg of 3^, 206.4pg of Y and 11 9.8pg of 3^, 206.4|jg of V and 14.7pg of y, 206.4(jg of V and 19.6|jg of y, 206.4[jg of V and 24.4jjg of 3^, 412.8jjg of V and 2.5|jg of y, 412.8|jg of 1^ and 4.9jjg of y, 412.8(jg of V and 9.8|jg of 3^, 412.8(jg of V and 14.7^9 of 3^, 412.8|jg of V and 19.6(jg of 3^, 412.8pg of V and 24.4pg of 3\ If the active substance combination wherein the salt 1 is the bromide and 3 denotes formoterol fumarate is used as a preferred combination of land 3 according to the invention, the quantities of active substances V and 3 administered per single dose as specified by way of example correspond to the following quantities of 1 and 3 10 administered per single dose: 10pg of 1 and 2.9pg of 3, 10pg of I and 5.7pg of 3, 10|jg of land 11.5jjg of 3, 10jjg of land 17.2|jg of 3, 10|jg of 1 and 22.9(jg of 3, 10(jg of 1 and 28.5|jg of 3, 20|jg of 1 and 2.9|jg of 3, 20|jg of 1 and 5.7jjg of 3, 20jjg of 1 and 11,5pg of 3, 20(jg of 1 and 17.2jjg of 3, 20|jg of 1 and 22.9|jg of 3, 20pg of 1 and 28.5|jg of 3, 40|jg of 1 and 2.9pg of 3, 40|jg of 1 and 5.7|jg of 3, 15 40pgof 1 and 11.5|jg of 3, 40pgof land 17.2(jg of 3, 40(jg of 1 and 22.9fjg of 3, 40|jg of 1 and 28.5pg of 3, 60(jg of 1 and 2.9pg of 3, 60[jg of 1 and 5.7|jg of 3, 60ijg of 1 and 11.5|jg of 3, 60|jg of 1 and 17.2jjg of 3, 60|jg of 1 and 22.9pg of 3, 60pg of 1 and 28.5pg of 3, 100|jg of 1 and 2.9pg of 3, 100fjg of t and 5.7|jg of 3, lOOpg of 1 and 11,5|jg of 3, 100pg of 1 and 17.2pg of 3, 100|jg of 1 and 22.9pg of 20 3, 100|jg of 1 and 28.5(jg of 3, 200(jg of 1 and 2.9[jg of 3, 200(jg of 1 and 5.7|jg of 3, 200[jg of 1 and 11.5[jg of 3, 200|jg of 1 and 17.2pg of 3, 200pg of 1 and 22.9yg of 3, 200pg of 1 and 28.5(jg of 3, 250|jg of 1 and 2.9pg of 3, 250|jg of 1 and 5.7(jg of 3, 250pg of 1 and 11.5|jg of 3, 250|jg of 1 and 17.2(jg of 3, 250(jg of 1 and 22.9(jg of 3, 250|jg of 1 and 28.5^ig of 3, 500pg of 1 and 2.9ng of 3, 500ng of 25 1 and 5.7[jg of 3, 500[jg of 1 and 11.5pg of 3, 500ijg of 1 and 17.2pg of 3, 500(jg of 1 and 22.9)jg of 3, 500|jg of 1 and 28.5(jg of 3.

If the active substance combination wherein 3 denotes formoterol fumarate dihydrate and the salt 1 is the bromide is used as a preferred combination of 1 and 3 30 according to the invention, the quantities of active substances V and 3^ administered per single dose as specified by way of example correspond to the following quantities of 1 and 3 administered per single dose: 10pg of 1 and 3|jg of 3, 10pg of 1 and 6pg of 3, 10pg of 1 and 12(jg of 3, 10pg of 1 and 18[jg of 3, 10pg of 1 and 24)jg of 3, 10jjg of 1 and 30(jg of 3, 20(jg of 1 and 3(jg of 3, 20|jg of 1 and 6}jg of 3, 20|jg of 35 1 and 12pg of 3, 20fjg of 1 and 18jjg of 3, 20(jg of 1 and 24pg of 3, 20pg of 1 and 30pg of 3, 40jjg of 1 and 3pg of 3, 40pg of 1 and 6pg of 3, 40pg of 1 and 12}jg of 3, 40pg of 1 and 18pg of 3, 40pg of 1 and 24pg of 3, 40pg of 1 and 30|jg of 3, 60|jg of 1 and 3pg of 3, 60pg of 1 and 6pg of 3, 60(jg of 1 and 12pg of 3, 60(jg of 1 and 18pg of 3, 60(jg of 1 and 24pg of 3, 60jjg of \ and 30|jg of 3, 10Opg of \ 12 and 3pg of 3, 100[jg of 1 and 6pg of 3, 100pg of 1 and 12pg of 3, 100(jg of 1 and 18pg of 3, 100|jg of 1 and 24pg of 3, 100[jg of 1 and 30|jg of 3, 200[jg of 1 and 3jjg of 3, 200(jg of 1 and 6|jg of 3, 200(jg of 1 and 12|jg of 3, 200pg of ± and 18jjg of 3, 200pg of \ and 24[jg of 3, 200(jg of 1 and 30pg of 3, 250(jg of 1 and 5 3(jg of 3, 250(jg of 1 and 6pg of 3, 250|jg of 1 and 12pg of 3, 250|jg of i and 18pg of 3, 250|jg of 1 and 24[jg of 3, 250|jg of 1 and 30|jg of 3, 500|jg of 1 and 3|jg of 3, 500jjg of 1 and 6|jg of 3, 500|jg of 1 and 12[jg of 3, 500|jg of 1 and 18|jg of 3, 500[jg of 1 and 24pg of 3, 500|jg of ! and 30|jg of 3.

In the case of salmeterol, for example, the active substance combinations according to the invention may contain Y and T in ratios by weight which are in the range from about 1:30 to 400:1, preferably 1:25 to 200:1, preferably 1:20 to 100:1, more preferably from 1:15 to 50:1, for example.

For example, and without restricting the scope of the invention thereto, the preferred combinations of ! and 3 according to the invention may contain the cation Y and salmeterol 31 in the following ratios by weight: 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1.

The pharmaceutical compositions according to the invention containing the combinations of 1 and 3 are normally used so that the cation Y and salmeterol 3^ are present together in doses from 5 to 5000|jg, preferably from 10 to 2000[jg, more 25 preferably from 15 to 1OOOpg, still more preferably from 20 to 800|jg, preferably ^ according to the invention from 30 to 750pg, preferably from 40 to 700pg.

For example, the combinations of 1 and 3 according to the invention contain an amount of Y and salmeterol 3^ such that the total dosage per single dose is about 30 15pg, 20(jg, 25pg, 30|jg, 35pg, 45pg, 50|jg, 55pg, 60|jg, 65(jg, 70pg, 75|jg, 80|jg, 85|jg, 90|jg, 95pg, 100pg, 105pg, 110|jg, 115jjg, 120pg, 125pg, 130|jg, 135jjg, 140pg, 145jjg, 150|jg, 155pg, 160jjg, 165jjg, 170yg, 175pg, 180ijg, 185pg, 190pg, 195pg, 200|jg, 205pg, 210|jg, 215yg, 220pg, 225pg, 230(jg, 235pg, 240(jg, 245|jg, 250(jg, 255pg, 260|jg, 265pg, 270|jg, 275pg, 280(jg, 285pg, 290pg, 295pg, 300pg, 35 305yg, 310pg, 315jjg, 320pg, 325pg, 330jjg, 335ijg, 340(jg, 345pg, 350pg, 355pg, 360[jg, 365|jg, 370|jg, 375(jg, 380pg, 385pg, 390|jg, 395pg, 400pg, 405|jg, 410|jg, 415pg, 420|jg, 425|jg, 430|jg, 435pg, 440(jg, 445pg, 450pg, 455|jg, 460ijg, 465|jg, 470(jg, 475(jg, 480pg, 485jjg, 490|jg, 495|jg, 500|jg, 505|jg, 510(jg, 515pg, 520(jg, 525pg, 530pg, 535pg, 540(jg, 545pg, 550pg, 555pg, 560pg, 565pg, 570|jg, 575pg, 13 580fjg, 585|jg, 590pg, 595{jg, 600pg, 605jjg, 610|jg, 615|jg, 620|jg, 625|jg, 630pg, 635|jg, 640(jg, 645(jg, 650|jg, 655|jg, 660|jg, 665pg, 670(jg, 675|jg, 680|jg, 685|jg, 690^, 695pg, 700pg or the like. It is clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the numerical 5 values explicitly mentioned. Fluctuations of around ± 2.5jjg, particularly fluctuations in the decimal range, are also covered as will be apparent to anyone skilled in the art. In these dosage ranges the active substances Y and 3^ are present in the weight ratios described above.

For example and without restricting the scope of the invention thereto, the combinations of 1 and 3 according to the invention contain an amount of cation Y and salmeterol 3^ such that they contain, per single dose, for example 8.3pg of Y_ and 12.5|jg of 3^, 8.3pg of Y and 25|jg of 3^, 8.3(jg of Y and 50(jg of y, 8.3[jg of Y and 75pg of y, 8.3(jg of Y and 100(jg of y, 8.3pg of Y and 200jjg of T, 16.5(jg 15 of Y and 12.5pg of T, 16.5|jg of Y and 25pg of y, 16.5pg of Y and 50pg of y, 16.5pg of Y and 75pg of 3^, 16.5|jg of Y and 100(jg of 3^, 16.5|jg of Y and 200(jg of 3^, 33.0[jg of Y and 12.5pg of 3^, 33.0pg of Y and 25pg of y, 33.0[jg of Y and 50|jg of 3^, 33.0|jg of Y and 75pg of y, 33.0|jg of Y and 100|jg of y, 33.0|jg of Y and 200(jg of y, 49.5pg of Y and 12.5pg of y, 49.5pg of Y and 25pg of y, 49.5pg 20 of Y and 50pg of 3^, 49.5jjg of Y and 75pg of 3^, 49.5|jg of Y and 100|jg of y, 49.5(jg of Y and 200|jg of 3^, 82.6pg of Y and 12.5(jg of y, 82.6|jg of Y and 25pg of y, 82.6pg of Y and 50(jg of 3^, 82.6pg of Y and 75pg of y, 82.6pg of Y and 100|jg of y, 82.6pg of Y and 200pg of y, 165.1 jjg of Y and 12.5pg of y, 165.1 |jg of Y and 25pg of T, 165.1 jjg of Y and 50|jg of 3^, 165.1 pg of Y and 75pg of 3^, 25 165.1 pg of Y and 10Opg of y, 165.1 (jg of Y and 200|jg of y, 206.4pg of Y and 12.5(jg of y, 206.4ijg of 1^ and 25pg of y, 206.4|jg of Y and 50pg of y, 206.4[jg of Y and 75pg of y, 206.4pg of Y and 100pg of y, 206.4(jg of Y and 200pg of y, 412.8pg of Y and 12.5jjg of y, 412.8pg of 1^ and 25pg of 3^, 412.8|jg of Y and 50pg of y, 412.8|jg of Hand 75[jg of y, 412.8(jg of Y and 100pg of y, 412.8pg of 30 r and 200pg of 3\ If the active substance combination wherein the bromide is used as the salt 1 and 3 denotes salmeterol xinafoate is used as a preferred combination of 1 and 3 according to the invention, the quantities of active substances Y and 3^ administered 35 per single dose as specified by way of example correspond to the following quantities of 1 and 3 administered per single dose: 10pg of 1 and 18.2jjg of 3, 10[jg of 1 and 36.3pg of 3, 10(jg of 1 and 72.6(jg of 3, 10(jg of ± and 108.9pg of 3, 10jjg of 1 and 145.2jjg of 3, 10(jg of 1 and 290,4pg of 3, 20pg of 1 and 18.2pg of 3, 20pg of 1 and 36.3|jg of 3, 20|jg of 1 and 72.6(jg of 3, 20|jg of 1 and 108.9(jg of 3, 20pg of 14 1 and 145.2[jg of 3, 20pg of 1 and 290.4|jg of 3, 40pg of 1 and 18.2(jg of 3, 40|jg of i and 36.3(jg of 3, 40|jg of 1 and 72.6|jg of 3, 40(jg of 1 and 108.9|jg of 3, 40jjg of i and 145.2(jg of 3, 40|jg of 1 and 290.4pg of 3, 60|jg of 1 and 18.2pg of 3, 60|jg of 1 and 36.3|jg of 3, 60pg of 1 and 72.6pg of 3, 60pg of 1 and 108.9pg of 5 3, 60pg of 1 and 145.2pg of 3, 60|jg of 1 and 290.4|jg of 3, 100pg of 1 and 18.2pg of 3, 100pg of i and 36.3|jg of 3, 100|jg of 1 and 72.6[jg of 3, 100|jg of 1 and 108.9pg of 3, 100|jg of 1 and 145.2pg of 3, 100pg of 1 and 290.4|jg of 3, 200|jg of 1 and 18.2pg of 3, 200jjg of 1 and 36.3|jg of 3, 200(jg of i and 72.6|jg of 3, 200|jg of 1 and 108.9|jg of 3, 200pg of 1 and 145.2|jg of 3, 200|jg of 1 and 290.4ijg of 3, 10 250(jg of 1 and 18.2|jg of 3, 250|jg of \ and 36.3|jg of 3, 250[jg of 1 and 72.6|jg of 3, 250pg of 1 and 108.9pg of 3, 250|jg of 1 and 145.2|jg of 3, 250|jg of 1 and 290.4|jg of 3, 500|jg of 1 and 18.2|jg of 3, 500|jg of 1 and 36.3|jg of 3, 500|jg of 1 and 72.6|jg of 3, 500|jg of 1 and 108.9pg of 3, 500(jg of 1 and 145.2pg of 3, | 500|jg of i and 290.4[jg of 3.

The quantities of active substance in the pharmaceutical combinations according to the invention can be calculated analogously if instead of salmeterol xinafoate the compounds 3 salmeterol-4-phenylcinnamic acid salt (4-phenylcinnamate) and salmeterol-5-(2,4-difluorophenyl)salicylic acid salt (5-(2,4-difluorophenyl)salicylate; 20 diflunisal) are used, which are equally preferred according to the invention.

The active substance combinations of 1, 2 and 3 according to the invention are preferably administered by inhalation. For this purpose, ingredients ! , 2 and 3 have to be made available in forms suitable for inhalation. Inhalable preparations include 25 inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the f combination of active substances i , 2 and 3 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention the term carrier may optionally 30 be used instead of the term excipient. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1, 2 and 3 either together in one formulation or in two or three separate formulations. These formulations which may be used within 35 the scope of the present invention are described in more detail in the next part of the specification.

A) Inhalable powder containing the combinations of active substances 1_ , 2 and 3 according to the invention: The inhalable powders according to the invention may contain 1 , 2 and 3 either on their own or in admixture with suitable physiologically acceptable excipients.

If the active substances 1, 2 and 3 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. 10 sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250(jm, preferably between 10 and 150pm, most preferably between 15 and 80pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9pm to the excipients mentioned above. These finer excipients are also selected from the group 20 of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance i, 2 and 3, preferably with an average particle size of 0.5 to 10|um, more preferably from 1 to 5|j,m, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and lastly mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both I and 2 and 3 or in the form of separate inhalable powders which contain only \ , 2 or 3.

The inhalable powders according to the invention may be administered using inhalers 30 known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1, 2 and 3 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. Preferably, the inhalable powders according to the invention 35 which contain physiologically acceptable excipients in addition to 1 , 2 and 3 are 16 packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.

A particularly preferred inhaler for using the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.

This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 10 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and air holes 13 for ^ adjusting the flow resistance.

If the inhalable powders according to the invention are to be packed into capsules (inhalers) for the preferred use described above, the quantities packed into each 15 capsule should be 1 to 30mg, preferably 3 to 20mg, more particularly 5 to 10mg of inhalable powder per capsule. These capsules contain, according to the invention, either together or separately, the doses of i, 2 and 3 mentioned hereinbefore for each single dose.

B) Propellant gas-driven inhalation aerosols containing the combinations of 20 active substances 1 , 2 and 3_ according to the invention: Inhalation aerosols containing propellant gas according to the invention may contain substances 1, 2 and 3 dissolved in the propellant gas or in dispersed form. 1 , 2 and f 3 may be present in separate formulations or in a single preparation, in which i, 2 and 3 are either each dissolved, dispersed or only one or two of the components is or 25 are dissolved and the other or others is or are dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The 30 propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG134a, TG227 and mixtures thereof. 17 The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants, preservatives and pH adjusters. All these ingredients are known in the art.

The inhalation aerosols containing propellant gas according to the invention may 5 contain up to 5 wt.-% of active substance 1 , 2 and/or 3. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 , 2 and/or 3.

If the active substances 1 , 2 and/or 3 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10jj,m, preferably 10 from 0.1 to 5|xm, more preferably from 1 to 5|j.m.

\ The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs = metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described 15 combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the 20 above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known ^ from the prior art.

C) Propellant-free inhalable solutions or suspensions containing the 25 combinations of active substances 1, 2 and 3 according to the invention: It is particularly preferred to use the active substance combination according to the invention in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative 30 proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of the volume is made up of water. The solutions or suspensions containing 1, 2 and 3, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted 35 using acids selected from inorganic or organic acids. Examples of suitable inorganic 18 acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are 5 hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, 10 antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the 15 present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100 mg/100ml, preferably less than 50mg/100ml, more preferably less than 20mg/100ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100ml are preferred.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the physiologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with 30 the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins 35 and/or other additives known in the art. The additives also include physiologically acceptable salts such as sodium chloride as isotonic agents. %25 19 The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.

Preservatives may be used to protect the formulation from contamination with 5 pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml.

Preferred formulations contain, in addition to the solvent water and the combination of active substances 1, 2 and 3, only benzalkonium chloride and sodium edetate. In ) another preferred embodiment, no sodium edetate is present.

The propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount 15 of a liquid formulation in the required therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred nebulisers are those in which a quantity of less than 100|aL, preferably less than 50|iL, more preferably between 20 and 30|iL of active substance solution can be nebulised in preferably one spray action to form an 20 aerosol with an average particle size of less than 20|jm, preferably less than lOpim, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.

^ An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International 25 Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are known by the name Respimat®.

This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 30 1,2 and 3. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient. The nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols.

The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a storage container, characterised by - a pump housing which is secured in the upper housing part and which - comprises at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow plunger with valve body, - a power takeoff flange in which the hollow plunger is secured and which is located in the upper housing part, - a locking mechanism situated in the upper housing part, - a spring housing with the spring contained therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction.

The hollow plunger with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to Figures 1 to 4, especially Figure 3, and the relevant parts of the description. The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of 10 to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred.

The valve body is preferably mounted at the end of the hollow plunger facing the nozzle body.

The nozzle in the nozzle body is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle bodies are disclosed for example in WO-94/07607; reference is hereby made to the contents of this specification, particularly Figure 1 therein and the associated description.

The nozzle body consists for example of two sheets of glass and/or silicon firmly joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the length is preferably 7 to 9 microns. 21 In the case of a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle openings at the outlet end the directions of spraying 5 may be at an angle of 20 to 160° to one another, preferably 60 to 150°, most preferably 80 to 100°. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred. The directions of spraying will therefore meet in the vicinity of the nozzle openings.

The liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.

The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member. The travel of the power takeoff flange is precisely limited by an upper and lower stop. The spring is preferably biased, via a 20 power step-up gear, e.g. a helical thrust gear, by an external torque which is produced when the upper housing part is rotated counter to the spring housing in the lower housing part. In this case, the upper housing part and the power takeoff flange have a single or multiple V-shaped gear.

The locking member with engaging locking surfaces is arranged in a ring around the 25 power takeoff flange. It consists, for example, of a ring of plastic or metal which is inherently radially elastically deformable. The ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of the locking member move into the path of the power takeoff flange and prevent the spring from relaxing. The locking member is actuated by means of a button. The 30 actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annular plane. Details of the construction of the locking mechanism are given in WO 97/20590. 22 The lower housing part is pushed axially over the spring housing and covers the mounting, the drive of the spindle and the storage container for the fluid.

When the atomiser is actuated the upper housing part is rotated relative to the lower housing part, the lower housing part taking the spring housing with it. The spring is 5 thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is biased, the power takeoff part in the upper housing part is moved along by a given distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as 10 a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle.

If desired, a number of exchangeable storage containers which contain the fluid to be atomised may be pushed into the atomiser one after another and used in succession. The storage container contains the aqueous aerosol preparation according to the 15 invention.

The atomising process is initiated by pressing gently on the actuating button. As a result, the locking mechanism opens up the path for the power takeoff member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.

Further details of construction are disclosed in PCT Applications WO 97/12683 and WO 97/20590, to which reference is hereby made.

The components of the atomiser (nebuliser) are made of a material which is suitable for its purpose. The housing of the atomiser and, if its operation permits, other parts as well, are preferably made of plastics, e.g. by injection moulding. For medicinal 25 purposes, physiologically safe materials are used.

Figures 2a/b attached to this patent application, which are identical to Figures 6a/b of WO 97/12687, show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention.

Figure 2a shows a longitudinal section through the atomiser with the spring biased while Figure 2b shows a longitudinal section through the atomiser with the spring relaxed. 23 The upper housing part (51) contains the pump housing (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end 5 the hollow plunger carries the valve body (58). The hollow plunger is sealed off by means of the seal (59). Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed. On the power takeoff flange is the stop (61) on which the power takeoff flange abuts when the spring is biased.

After the biasing of the spring the locking member (62) moves between the stop (61) 10 and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon.

The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-in lugs (69) and rotary bearing. The lower 15 housing part (70) is pushed over the spring housing. Inside the spring housing is the exchangeable storage container (71) for the fluid (72) which is to be atomised. The storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of active substance solution).

The spindle (74) for the mechanical counter is mounted in the covering of the spring housing. At the end of the spindle facing the upper housing part is the drive pinion (75). The slider (76) sits on the spindle.

The nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to produce an aerosol suitable for inhalation.

If the formulation according to the invention is nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of 30 formulation are delivered as a defined mass on each actuation.

However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers. 24 Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®. Preferably, the invention relates to propellant-free 5 inhalable solutions or suspensions characterised by the combination of active substances ^ 2 and 3 according to the invention in conjunction with the device known by the name Respimat®. In addition, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to 10 the invention as described hereinbefore.

The propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may be produced from the 15 concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.

Accordingly, in another aspect, the present invention relates to pharmaceutical 20 compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.

The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention to the following embodiments by way of example.

Examples of Formulations A) Inhalable powders: 1) Ingredients pg per capsule Ij-bromide 100 budesonide 200 salmeterol xinafoate 55.9 lactose 4721.6 Total 5000 2) Ingredients pg per capsule l>bromide 75 fluticasone propionate 125 salmeterol-4-phenylcinnamate 50 lactose 4802.5 Total 5000 3) Ingredients pg per capsule I'-bromide 75 mometasone furoate 250 formoterol fumarate dihydrate 12 lactose 4715.5 Total 5000 4) Ingredients pg per capsule I'-bromide 100 fluticasone propionate 250 formoterol fumarate dihydrate 12 lactose 4715.5 Total 5000 26 ) Ingredients |jg per capsule V-bromide 200 formoterol fumarate dihydrate 12 fluticasone propionate 250 lactose 24538 Total 25000 6) Ingredients |jg per capsule V-bromide 75 fluticasone propionate 125 salmeterol-diflunisal 50 lactose 4802.5 Total 5000 B) Inhalable aerosols containing propellant gas: 1) Suspension aerosol: Ingredients Wt-% I'-bromide 0.035 budesonide 0.4 formoterol fumarate dihydrate 0.066 soya lecithin 0.2 TG 134a : TG227 = 2:3 ad 100 2) Suspension aerosol: Ingredients Wt-% 1'-bromide 0.039 fluticasone propionate 0.3 salmeterol xinafoate 0.033 isopropyl myristate 0.1 TG 227 ad 100 27 pension aerosol: Ingredients Wt-% 1>bromide 0.039 mometasone furoate 0.6 salmeterol x diflunisal 0.066 isopropyl myristate 0.1 TG 227 ad 100 4) Suspension aerosol: Ingredients Wt-% I'-bromide 0.035 fluticasone propionate 0.3 salmeterol 4-phenylcinnamate 0.066 soya lecithin 0.2 TG 11 : TG12 = 2:3 ad 100 ) Suspension aerosol: Ingredients Wt-% 1'-bromide 0.039 salmeterol xinafoate 0.033 budesonide 0.4 absolute ethanol 0.5 isopropyl myristate 0.1 TG 227 ad 100

Claims (1)

1. 28 What is claimed is A pharmaceutical composition for inhalation, which contains at least one anticholinergic of formula 1 wherein X" denotes an anion with a single negative charge, at least one corticosteroid (2) and at least one betamimetic (3), optionally in the form of an enantiomer, mixture of the enantiomers or in the form of a racemate thereof, optionally in the form of a solvate or hydrate and optionally together with a physiologically acceptable excipient. A pharmaceutical composition according to claim 1, wherein the anion is selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate. Pharmaceutical composition according to claim 1 or 2, wherein the active substances 1, 2 and 3 are present either together in a single formulation or in two or three separate formulations. Pharmaceutical composition according to any one of claims 1 to 3, wherein 1 is selected from the group of salts wherein X - is a negatively charged anion selected from the group consisting of chloride, bromide, 4-toluenesulphonate and methanesulphonate. Me + Me \ / X Me 0FN.7 3 1 JUL 2007 receivto 29 5) Pharmaceutical composition according to claim 4, wherein X - is bromide. 6) Pharmaceutical composition according to any one of claims 1 to 5, wherein 2 is selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. 7) Pharmaceutical composition according to claim 6, wherein 2 is selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone. 8) Pharmaceutical composition according to any one of claims 1 to 7, wherein 3 is selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1 -(2-fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyI]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol. 9) Pharmaceutical composition according to claim 8, wherein 3 is selected from among formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, imjfiifrtual property office of n.z. 31 JUL 2007 received 30 10) 11) 12) 13) 1 -(2-fluoro-4-hydroxyphenyl)-2-[4-(1 -benzimidazolyl)-2-methyl-2-butylaminojethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1 -[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanoI and 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol. A pharmaceutical composition according to any one of claims 1 to 9, wherein the weight ratios of V Me. + Me \ / N and 2 are in the range from 1:250 to 250:1. Pharmaceutical composition according to claim 10, wherein the weight ratios of V and 2 are in the range from 1:150 to 150:1. Pharmaceutical composition according to any one of claims 1 to 11, wherein the weight ratios of 1 to 3 are in the range from 1:300 to 30:1. Pharmaceutical composition according to claim 12, wherein the weight ratios of 1_to 3 are in the range from 1:230 to 20:1. intellectual property office of n.z. 3 1 JUL 2007 Dcr.Pi\/FD 31 14) Pharmaceutical composition according to any one of claims 1 to 13, wherein a single administration corresponds to a dose of the active substance combination 1, 2 and 3 of 1 to 10000}jg. 15) Pharmaceutical composition according to claim 14, wherein the single administration corresponds to a dose of the active substance combination 1, 2 and 3 of from 10 to 2000|jg. 16) Pharmaceutical composition according to any one of claims 1 to 10, in the form of a formulation suitable for inhalation. 17) Pharmaceutical composition according to claim 16, wherein it is a formulation selected from among inhalable powders, propellant-containing metering aerosols and propellant-free inhalable solutions or suspensions. 18) Pharmaceutical composition according to claim 17, wherein it is an inhalable powder which contains 2 and 3 in admixture with suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients. 19) Inhalable powder according to claim 18, wherein the excipient has a maximum average particle size of up to 250^im. 20) Inhalable powder according to claim 19, wherein the excipient has a maximum average particle size of between 10 and 150 (jm. 21) A capsule, which contains an inhalable powder according to any one of claims 18 to 20. 22) Pharmaceutical composition according to claim 17, wherein it is an inhalable powder which contains only the active substances 1^ 2 and 3 as its ingredients. 23) Pharmaceutical composition according to claim 17, wherein it is a propellant-containing inhalable aerosol which contains 1^ 2 and 3 in dissolved or dispersed form. intellectual property office of n.z. 3 1 JUL 2007 receive!- f 'i. 32 24) Propellant-containing inhalable aerosol according to claim 23, wherein it contains, as propellant gas hydrocarbons or halohydrocarbons. 25) Propellant-containing inhalable aerosol according to claim 24, wherein the hydrocarbon is n-propane, n-butane or isobutane. 26) Propellant-containing inhalable aerosol according to claim 24, wherein the halohydrocarbon is chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. 27) Propellant-containing inhalable aerosol according to claim 24, wherein the propellant gas is TG134a, TG227 or a mixture thereof. 28) Propellant-containing inhalable aerosol according to any one of claims 23 to 27, wherein it optionally contains one or more other ingredients selected from among cosolvents, stabilisers, surfactants, antioxidants, lubricants and means for adjusting the pH. 29) Propellant-containing inhalable aerosol according to any one of claims 23 to 28, wherein it may contain up to 5 wt.-% of active substance 1, 2 and/or 3. 30) Use of a capsule according to claim 21 in an inhaler. 31) Use of a composition according to any one of claims 1 to 29 for preparing a medicament for treating inflammatory or obstructive diseases of the respiratory tract. 32) Use of a composition according to claim 31 for preparing a medicament for treating asthma or COPD. 33) A pharmaceutical composition as defined in any one of claims 1 to 18, 22 or 23, substantially as hereinbefore described and with reference to the Figures and/or Examples. 34) An inhalable powder as defined in claim 19 or 20, substantially as hereinbefore described and with reference to the Figures and/or Examples. INTELLECTUAL PROPERTY OFFICE OF N.Z 21 AUG 2007 received 33 35) A capsule as defined in claim 21, substantially as hereinbefore described and with reference to the Figures and/or Examples. 36) A propellant-containing inhalable aerosol as defined in any one of claims 24 to 29, substantially as hereinbefore described and with reference to the Figures and/or Examples. 37) A use as defined in any one of claims 30 to 32, substantially as hereinbefore described and with reference to the Figures and/or Examples. end of claims intellectual property office of n.z. 3 1 JUL 2007 received